Clinical Implications of DNA Repair Defects in High-Grade Serous Ovarian Carcinomas

Abstract

Despite significant improvements in surgical and medical management, high grade serous ovarian cancer (HGSOC) still represents the deadliest gynecologic malignancy and the fifth most frequent cause of cancer-related mortality in women in the USA. Since DNA repair alterations are regarded as the "the Achille's heel" of HGSOC, both DNA homologous recombination and DNA mismatch repair deficiencies have been explored and targeted in epithelial ovarian cancers in the latest years. In this review, we aim at focusing on the therapeutic issues deriving from a faulty DNA repair machinery in epithelial ovarian cancers, starting from existing and well-established treatments and investigating new therapeutic approaches which could possibly improve ovarian cancer patients' survival outcomes in the near future. In particular, we concentrate on the role of both Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPis) and immune checkpoint inhibitors in HGSOC, highlighting their activity in relation to BRCA1/2 mutational status and homologous recombination deficiency (HRD). We investigate the biological rationale supporting their use in the clinical setting, pointing at tracking their route from the laboratory bench to the patient's bedside. Finally, we deal with the onset of mechanisms of primary and acquired resistance to PARPis, reporting the pioneering strategies aimed at converting homologous-recombination (HR) proficient tumors into homologous recombination (HR)-deficient HGSOC.

Keywords: BRCA reversion mutations; DNA homologous recombination; DNA mismatch repair; DNA repair deficiency; PARP inhibitors; epithelial ovarian cancer.

Figure 1

Distribution of homologous recombination deficiency (HRD) genes’ mutations in high grade serous ovarian cancers (HGSOCs): (a) germline mutations; (b) somatic mutations (data from The Cancer Genome Atlas [1]).

Figure 1

Distribution of homologous recombination deficiency (HRD) genes’ mutations in high grade serous ovarian cancers (HGSOCs): (a) germline mutations; (b) somatic mutations (data from The Cancer Genome Atlas [1]).

Figure 2

Schematic illustration of synthetic lethality. The concomitant alteration of two genes (defined as A and B), generally involved in complementary pathways, leads to cell death, while loss of function of only one of them does not. Synthetic lethality exploits the notion that the presence of a mutation in a cancer gene is often associated with a new vulnerability that can be targeted therapeutically.

Figure 3

Mechanisms of resistance to PARPis. (A) BRCA-dependent mechanisms: (upper part) appearance of secondary “revertant” BRCA mutations (favored by increased DNA mutation rate) that restore the open reading frame and allow the synthesis of a functional BRCA protein; (lower part) PARPi-induced selection of pre-existing cells with “revertant” BRCA mutations. (B) BRCA-independent mechanisms: (from top to bottom) loss of PARP1 expression (often due to epigenetic mechanisms); appearance of PARP1 mutations altering PARP1 trapping; inactivation of the DNA repair proteins 53BP1 or REV7, resulting in the restoration of homologous recombination repair; increased expression of multidrug resistance proteins.

Figure 4

Ovarian cancer (OC) tumor evolution under treatment with HR-synthetic lethal agents and new insights into novel therapeutic approaches aiming at disrupting HR proficiency in OC. Legend. Blue circle: HR-deficient ovarian cancer cell; Red star: HR-proficient ovarian cancer cell; OC: Ovarian Cancer; HR: Homologous Recombination; ChT: Chemotherapy; PARPis: Poly (ADP Ribose) Polymerase Inhibitors; CDK1is: Cyclin-Dependent Kinase 1 inhibitors; PI3Kis: PhosphoInositide 3-Kinase inhibitors; BETis: Bromodomain and Extraterminal Domain inhibitors; HDACis: Histone DeACetylase inhibitors.